5,5-Diphenyl-3-(piperidino, tetrahydropyridyl-1-and piperazino)-hydantoins

ABSTRACT

3-substituted-5,5-diphenylhydantoin derivatives in which the 5,5-diphenylhydantoin moiety is attached at C3 by a loweralkylene bridge to a 4-phenyl-1-piperidyl, 4-hydroxy-4-phenyl-1-piperidyl, 4-phenyl-1,2,3,6-tetrahydropyridyl, 4-phenyl-1-piperazinyl, or loweralkylamino group are useful in the treatment of cardiac arrhythmias in mammals. One or both of the 5,5-diphenyl substituents optionally can be substituted in the ortho-, meta-, or para-positions with halogeno, loweralkyl, loweralkoxy, amino or nitro groups.

United States Patent [191 Hayao et al.

[ 5,5-DIPHENYL-3-(PIPERIDINO, TETRAHYDROPYRIDYL-l-ANDPIPERAZINO)-HYDANTOINS [75] Inventors: Shin Hayao, Tokyo, Japan; HerbertJohn Havera, Edwardsburg, Mich; Wallace Glenn Strycker, Goshen,

Ind.

[73] Assignee: Miles Laboratories, Inc., Elkhart,

Ind.

[22] Filed: July 20, 1973 21 Appl. No.: 381,021

[52] US. Cl. 260/268 PH; 260/293.7; 260/295 D; 260/295 L; 260/309.5;424/250 [51] Int. Cl C07d 51/70 [58] Field of Search 260/268 PH, 309.5,293.7, 260/295 SP, 293.66, 295 D, 295 L [56] References Cited OTHERPUBLICATIONS Chiti et al. Chemical Abstracts Vol. 55, p. 21,100, (1961).

Hi] 3,892,748 [451 July 1,1975

Zejc, Alfred Chemical Abstracts Vol. 70, p. 3778021, (1969).

Primary ExaminerDonald G. Daus Assistant ExaminerJose Tovar Attorney,Agent, or FirmMyron B. Sokolowski [5 7 ABSTRACT 16 Claims, No Drawings,5-DIPHENYL-3-PIPERIDINO TETRAHYDROPYRIDYL-l -AND PIPERAZINO)-HYDANTOINS BACKGROUND OF THE INVENTION l. Field of the Invention Y 1Cardiac arrhythmias are disorders of impulse generation in the mammalianheart. Although the physiological mechanisms of these disorders are notcompletely understood, they are believed to result from disruptions ofnormal cardiac pacemaker activity, disturbances in the cardiacconductive fibers. or a combination of the former and latter factors.Cardiac arrhythmias of clinical significance in man include: (A)premature contractions (extra -systoles) having their origin in abnormalfocal points in the atria or ventricles, (B) paroxysmal supraventriculartachycardia, (C) atrial flutter, (D) atrial fibrillation, (E)ventricular tachycardia, and (F).ventricular fibrillation. Thesearrhythmias can be induced in experimental animals to studyphysiological mechanisms involved in such arrhythmias or to screen newantiarrhythmic agents.

Arrhythmias are treated clinically by administration of a variety ofdrugs, although quinidine and procainamide are current mainstays.Quindine is the d-isomer of quinine while procainamide is p-amino N(2-diethylamino-ethyl)-benzamide. Both drugs require extreme care inadministration and are considered relatively dangerous. In Weighingtheir efficacy over their danger, however, the former is countervailing.Because of such limitations in currently available antiarrhythmic drugs,there havebeen effortsto discover safer substitutes. The discovery ofthe antiarrhythmic activity of hydantoin opened new approaches in thedesign of new compounds exhibiting suchactivity. For a generaldiscussion of this field, to which the instant invention pertains, referto G. K. Moe and J. A. Albild skov, Antiarrhythrnic Drugs/Y. in: ThePharmacological Basis of Therapeutic L. S. Goodman andA. Gilman,Editors, 4th Edition, The MacMiIIan Company, New York, Chapter 32 19702. Description of the Prior Art U.S. Pat. No. 2,409,754 (1954) disclosesthe synthesis and structure of diphenylhydantoin or 5,5-diphenyl-2,4-imidazolidinedione, which is represented by Formula I:

Diphenylhydantoin (hereafter referred to as DPH) was utilized initiallyin the treatment of epilepsy, but was discovered later to have importantantiarrhythmic applications. Of particular interest to scientists andclinicians was that the pharmacodynamics of DPH differed from quinidineand procainamide, and that DPH did not exhibit the dangerous propertiesof its precursors. DPH was found specifically to antagonize ventriculararryhthmias induced by digitalis. In its action on the heart, DPHdepresses ventricular automaticity, enhances atrio-ventricular nodalconduction, and reduces the effective refractory period. DPH, however,is not without untoward side effects: dizziness, nausea, emesis,nystigmus, and ataxia. Large doses may produce atrio-ventricularblockade brady'cardia, or even cardiac arrest. For a review of thecurrent status of DPH as an antiarrhythmic agent, see L. S. Dreifus andY. Watanabe, Amer. Heart .I., 709-713 (I970).

There have been several attempts'to improve the activity and toeliminatethe side effects of DPH. Henze and lsbell (J. Amer. Chem. Soc.,.76: 4l52-4l56 [1954]) described twelve 5-(substitutedphenyl)- and5,5-di(substituted-phenyl)-hydantoins. Of these compounds, only5-(4-aminophenyl)-5-phenylhydantoin displayed activity, but only to theextent of 50% of DPH. W. Chiti and P. Chiarini (II. Farmaco, Sci. Ed.,13: 579-589 [1958]) synthesized seventeen derivatives of DPH, thefollowingthree of which are representatrve:

A. 3-(3-diethylaminopropyl)-5,S-diphenylhydantoin,

B. 3-[3-( l-piperidyl)propyl]-5,5-diphenylhydantoin,

N-(CH 3 L H O and C. 3-(3-morpholinopropyl)-5,5-diphenylhydantoin,

in antiarrhythmic activity and cause less cardiac de-' pression thenDPHor derivatives II, III, and IV.

SUMMARY This invention relates to compounds of the formula 3 andpharmacologically acceptable, nontoxic, acid addition salts thereof. Thesymbols R, R R, and R in Formula V are defined as follows:

R and R may be hydrogen, halogeno, loweralkyl of l to 3 carbon atoms,lowcralkoxy of l to'*3 carbon atoms, amino, or nitro. and may be locatedat the ortho-, meta-, or para-position of the phenyl moieties; R may bemethylene, ethylene, trimethylene, 2- hydroxy -trimethylene,tetramethylene, or 2-hydroxy'- tetramethylene; and i R may be4-phenyl-1-piperidy1, 4-hydroxy-4-phen'yll-piperidyl,4-pheny1-1,2,3,6-tetrahydropyridyl, 4- phenyl -l-piperazinyl, loweralkylamino of l to'4 carbon atoms, and diloweralkylamino of 2 to 8 carbonatoms. h

Compounds represented by V are synthesized by the method of Hoffman(Bull. Soc, Chim., pp 17 [1950]):

In VI and VII, R, R R and R have the same meaning as defined in V, and Jis either chlorine or bromine. The starting material, V1, is preparedaccording to the method disclosed by H. Henze and A. lsbell (JQAm. Chem.Soc., 76: 4152-4156 [1954]) or by the synthesis described by J. Meltonand H. Henze (J. Am. Chem. Soc., 69: 2018-2020 1947] Compoundsrepresented by Vll are prepared by methods well known in organicchemistry.

An alternate synthesis involves: 1 reaction ofa substituted amine, Vlll,to form a corresponding derivative or urea, IX; and (2) reaction of theurea derivative, IX, with benzil or substituted-benzil, X: i

Details of this alternate synthesis and the starting materials VIII andX are described by H. Hatt, et al., (J. Chem. Soc., pp 9396 [1936]) andby W. Dunnavant and F. James (J. Am. Chem. Soc., 78: 2740-2743 [1956]).

Pharmacologically acceptable, nontoxic acid addition salts of V areprepared by standard methods. Preferably hydrochloric. maleic, or oxalicacids are utilized.

The following compounds are representative of V; 1.3-[3-(4phenyl-1-piperazinyl)propyl]5,5-diphenyl -hydantoin maleate (MA1586);

3-[3-(4-phenyl-l-piperidyl)propyl]-5,5-diphenyl -hydantoin (MA 1598);

3. 3-[2-(4-phenyl-1piperidyl)ethyl]-5,5-diphenyl -hydantoinhydrochloride (TR 2906);

. 5,5-diphenyl-3-[2-(4-phenyl-l,2,3,6-

tetrahydropyridyh ethyl]hydantoin hydrochloride 5.5,5-diphenyl-3-[3-(4-hydroxy-4-phenyl-l-piperidyl) propyllhydantoinhydrochloride (TR 2916);

6. 3-(3-t-butylamino-2-hydroxypropyl)-5,5-diphenyl -'hydantoinhydrochloride (TR 2921 "I.5,5-diphenyl-3-[2-(4-hydroxy-4-phenyl-l-piperidyl) ethyl]hydantoinhydrochloride (TR 2951);

8. 3-[3-(4-phenyl-1piperidyl)propyl]-5,5-di(4-chloro -phenyl)hydantoinhydrochloride (TR 2984);

3-[3-(4-phenyl-1-piperidyl)propyl]-5(4-methoxy-phenyl)-5-phenylhydantoin hydrochloride (TR methoxy bromophenyl) (TR2987);

12. 3-[ 3-(4-pheny1- l -piperidyl )propyl]-5-phenyl-5-(4-tolyl)hydantoin maleate (TR 2993);

13. 3-[3-(4-phenyl-l-piperidyl)propyl]5,5-di(4-tolyl) hydantoin (TR3001);

14. 3-[ 3-(4-phenyl- 1 -piperidyl )propy1]-5-(4- nitrophenyl)-5-phenylhydantoin (TR 3012);

3-[ 3-( 4-phenyll -piperidyl )propyll-S ,5-di( 4- -phenyl)hydantoinhydrochloride (TR 3-[3-(4-phenyl-1-piperidyl)propyl]-5-(4--5-phenylhydantoin hydrochloride (1) R 2 ,KOH. -r .R -R nacowa (VIII)(Q9 z R3-R2NHCONH I t 2 101 15. 3-[ 3-( 4-phenyl- 1 -piperidyl )propyl]-5-( 4- aminophenyl) -5-phenylhydantoin (TR 3021): 16.5,5-diphenyl-3-l2-hydroxy-3-(4-Phenyl-1 piperidyl) propyl]-hydantoinoxalate (TR 3104);

17. 5,5-di-(4-tolyl)-3-[2-hydroxy-3(tbutylamino)propyll-hydantoinhemioxalate (TR 3130); and

18. 3-[3-(4-hydroxy-4-phenyl-1-piperidyl)propyl]-5,5- di-(4-tolyl)hydantoin (TR 3163). Compounds having formula V are moreeffective for the treatment of cardiac arrhythmias and causeconsiderably less cardiac depression than diphenylhydantoin or the priorart diphenylhydantoin derivatives 11, III,

and IV (Cf. Description of the Prior Art, above). De-

tails of the pharmacology of the compounds listed above are found inExamples 19 and in the following section, Description of the PreferredEmbodiments.

This invention also pertains to a method of treating a human or othermammal having a cardiac arrhythmia which comprises administering to saidhuman or other mammal an effective amount of a compound of formula V ora nontoxic pharmacologically acceptable acid addition salt thereof. Saidcompounds may be administered orally, rectally, intravenously,parenterally, intramuscularly, intraperitoneally or by other routes ofadministration. By an effective amount is meant a dose which is requiredto correct the arrhythmia to normal or near-normal cardiac rhythm and tomaintain such rhythm. This amount may range from 5 to 500 mg per day,depending on the severity of the cardiac arrhythmia and upon the weightof the human or other mammal to whom or which the compounds areadministered.

DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLE 1 3-[3-(4-phenyl-1-piperazinyl)propy1]-5,S-diphenyl -hydantoin maleate (MA1856). 5 ,5- diphenylhydantoin, 25.2 g (0.1 mole), was added to asolution of 2.3 g (0.1 mole) of sodium in 300 ml of anhydrous ethanoland the suspension was heated under reflux for half an hour.4-phenyl-1-(3-chloropropyl)- piperazine, (23.9 g, 0.1 mole) slowly wasadded to the suspension and the mixture was heated under reflux withstirring for 16 hours. The solvent was removed in vacuo, the concentratewas suspended in water, and the free base was extracted with chloroform.The dried extracts were concentrated in vacuo to an oil. The oil wasdissolved in hot methanol and 14 g (0.12 mole) of maleic acid was added.The hot solution was filtered and the filtrate was cooled. The resultingsolid was collected and recrystallized from an aqueous-methanolsolution. Yield: 32 g (56.2%); m.p., 212213.5 (dec.).

Calculated fQl CggHgoNqOg, C4H404i C, H,

Found: C, 67.85; H, 6.28; N, 9.90

EXAMPLE 2 Preparation of 3-[3-(4-phenyl-l-piperidyl)propyl]-5,5-diphenylhydantoin (MA 1598). 25.2 g (0.1 mole) of 5,5-diphenylhydantoin was added to a solution of 2.3 g (0.1 mole) of sodiumin 350 ml of anhydrous ethanol, and the suspension was heated underreflux with stirring for half an hour. 4-phenyl-1-(3-ch1oropropylpiperidine, 23.8 g (0.1 mole) was added, and the mixture was heatedunder reflux with stirring for 18 hours.

(dec.).

Calculated for C H N O H 0 C, 69.60; H,

6.15; N, 7.38 Found: C, 69.31; H, 6.18; N, 7.57

EXAMPLE 3 I 3-[2-(4-phenyll-piperidyl)ethyl]-5,5- diphenylhydantoinhydrochloride (TR 2906). 5.5- diphenylhydantoin (12.5 g, 0.05 mole) wasadded to sodium ethoxide (0.1 mole) in 350 ml of anhydrous ethanol. Themixture was heated to boiling and l-(2- chloroethyl)-4-phenylpiperidineHCl (13 g. 0.05 mole) was added. The mixture was refluxed with stirringfor 16 hours, filtered, anddiluted with H O to form a white solid.Yield: 11.5 g (52.3%); m.p., 7.

Calculated for C H N O C, 76.52; H, 6.65; N,

9.56 Found: C, 76.00; H, 6.72; N, 9.25 The free base (1 1.5 g, 0.026mole) was converted to the HCl salt with HClg/2-propanol, concentratedand crystallized in acetone. The solid was recrystallized twice from2-propanol-ether and again from methanolether. Yield: 6.5g (52%); m.p.,l93-4 (dec.).

Calculated for C ,,H N O HCl: C, 70.65; H, 6.34;

N, 8.82 j Found: C, 71.31; H, 6.23; N, 8.82

EXAMPLE 4 5,5-diphenyl3-[2-(4-pheny1- 1,2,3,6- tetrahydropyridyl)ethyl]hydantoin hydrochloride (TR 2913). 5,5-diphenyl -hydantoin (12.5g, 0.05 mole) was added to sodium ethoxide (0.1 mole) in 350 ml ofanhydrous ethanol. The mixture was heated to boiling and1-(2-chloroethy1)-4-phenyl-1 ,2,3,6- tetrahydropyridine HBr (16 g, 0.05mole) was added. The mixture was refluxed with stirring for 16 hours,filtered and diluted with H O to form a white solid. Yield: 14 g (64%);m.p., 211-3.

Calculated for C ,,H N O C, 76.82; H, 6.22; N,

Found: C, 77.12; H, 6.32; N, 9.34

The free base (10 g, 0.032 mole) was converted to the hydrochloride saltwith methanol and HClg/2- propanol, filtered and diluted withethylacetate. Yield: 7.3 g (48.2%); m.p., 2302 (dec.).

Calculated for C H N O HCl: C, 70.95; H, 5.95;

N, 8.86 Found: C, 70.96; H, 5.98; N, 8.78

EXAMPLE 5 5,5-diphenyl-3-[3-(4-hydroxy 4-pheny1-l-piperidyl)propyl]hydantoin hydrochloride (TR 2916). (A) N- 3(4-hydroxy-4-phenyl-l-piperidyl)propyl urea. KOH

(5.6 g) and KCNO (8.1 g) in H O were added to a solution of l-(3-aminopropyl) -4hydroxy4- phenylpiperidine ZHCl (30.7 g, 0.1 mole) in HO. The mixture was stirred for an hour and concentrated in vacuo todryness. The solid was recrystallized from 2- propanol-Skelly B. Yield:10 g, (3671): m.p., l623.

Calculated for C, H- ,,,N,,O- C, 65.00; H, 8.30; N.

Found: C, 64.86; H. 8.51; N. 14.86

B. A mixture of N-3-(4-hydroxy-4-phenyl-lpiperidyl)propyl urea g, 0.036mole). benzil (3.8 g. 0.018 mole), 50 ml of ethanol and 1 l cc of 66%KOH was warmed to form a solution and let stand at room temperature for1 hour. The solution was acidified with cone. HCl and concentrated. Theconcentrate was dis solved in hot aqueous ethanol, filtered and basifiedwith dilute Na CO solution. The crude solid was recrystallized fromaqueous MeOH. Yield: 7 g (41%); m.p., l74-5.

Calculated for C ,,H N O C, 74.18; H.

8.95 Found: C, 75.68; H. 6.70;N, 8.96

The free base (7 g, 0.015 mole) was converted to the HCl'salt withHCl/2-propanol-ethylacetate and recrystallized from methanol-ether.Yield: 6.5 g (86% m.p., 2l3-4 (dee.). I

Calculated for C- ;;,H;,,N;,O;,.HC1: C, 68.83; H. 6.36; N, 8.30 I Found:C. 68.92; H, 6.38; N, 8.30

EXAMPLE 6 3-(3-t-hutylamino-2-hydroxypropyl)-5.5-diphenyl -hydantoinhydrochloride (TR 2921). 5,5- diphenylhydantoin (12.6 g, 0.05 mole) wasadded to sodium ethoxide (0.05 mole) in hot anhydrous ethanol.Epichlorohydrin (6 g) was added to this hot solution and the mixture wasrefluxed for 3 hours. concentrated and diluted with H O. The mixture wasextracted with CHCl and the extracts were dried MgSO and concentrated todryness. The concentrate and 40 ml of t- BuNH in methanol were refluxedfor 2 hours and concentrated to dryness. The concentrate wascrystallized from benzene-Skelly B and recrystallized from benzene.Yield: 10 g (52.5%); m.p.. 159l60.

Calculated for C H N O C,69.27 H, 7.13

Found: C.'69.76; H, 7.32 I i The free base (10 g. 0.026 mole) wasconverted to the HCl salt with HClg/Z-propanol and the solid wasrecrystallized from methanol-ethylacetate. Yield: 6.5 g, (59.67:); m.p.,28l3 (dee.).

Calculated for C H- N -,O,,.HCI: C. 63.20; H. 6.75;

Found: C, 63.34; H, 6.69; N. 10.16

EXAMPLE 7 v5,5-diphenyl-3-l2-(4-hydroxy-4-phenyl-l-piperidyl)ethyl]hydantoin hydrochloride (TR 2921). Concl HCl (6.5 g) was added tol-(2-aminoethyl)-4-hydroxy-4- 8 made basic with dilute NaHCO and thesolid was collected and recrystallizedfrom aqueousdimethylformamide-methanol and again from aqueous-Dioxane. Yield: 11 g(31.8% m.p., 214' 5.

Calculated for CggHggNgOg: C, 73.83; H, 6.41; N,

9.22 Found: C, 74.14; H, 6.52; N, 9.30 The free base (10 g, 0.022 mole)in methanol-ethyl aeetate was converted to the HCl salt with HCI /Z-propanol and ether. The salt was recrystallized from 2- propanol-methanol-ether. Yield: 6.6 g (61%); 241-2 (dee.). 1

Calculated for C ,,H N O HCl: C, 68.36;-H, 6.15;

H, 8.54 v Found: C, 68.4jl; H, 6.18; N, 8.47

:EXAMPLE 8 3-l3-(4-phenyl-lpiperidyl)propyl]-5,5-di(4-chlorop'henyl)hydantoin'hydrochloride (TR 2984). 5,5-di(4- chloro-phenyl)hydantoin (8 g, 0.025 mole) was added tosodium ethoxide (0.05mole) in 300 ml of warm anhydrous I ethanol. l-(3-chloropropyl)-4,-phenylpiperidine HCl (6.8g, 0.025 mole) was added and the mixture wasrefluxed with stirring for 18 hours, filtered and diluted with H O. Thesolid was recrystallized from aqueous methanol-dimethylformamide andagain from'aqueous ethanol. Yield: 10.0 g (76.5%); m. p.,1 912. f.

Calc ulated for c ,,H,.,c1 N,o c, 66.67 H. 5.60; N, i 8.04

Found: (2, 66.46; H, 5.60; N, 7.96 I

The free base (10 g, 0.019 mole in hot anhydrous ethanol wasconverted-to the HCl salt with HCl/2- propanol and ether. Thesaltwasrecrystalliz'ed from 2- propanol -methanol-ether. Yield:'9.5 g(89%); m.p., 245-7 (dee.). i 1

Calculated for C ,,H Cl N O HCl: C, 62.31; -H, 5.41; N, 7.52 1 Found: C,62.36; H, 5.31; N, 7.26

.. EXAMPLE 9 (TR 2985). 5-(4-methoxy -phenyl)-5-phenylhydantoin (7.0 g,0.025 mole) was added to sodium ethoxide (0.05 mole) in 350 ml ofanhydrous ethanol. After warming 1 for 30 minutes, 1-(3-ehloroprobyl)Q4- phenyl'piperidine HCl (6.8 g, 0.025 mole) was added and the mixturewas refluxed with stirring for 18 hours, filtered and diluted with H O.The solid was collected and recrystallized from aqueous 2-propanol.Yield: 9 g (74.6%; m.p., 1346.

Calculated for C H N O C, 74.51;H, 6.88; N, 8.69 Found: c, 73.55; H,6.85; N, 8.48 1 The free base (8.8 g, 0.018 mole) in hot anhydrousethanol was converted to the HCl salt with HCl,/2- propanol and ether.The saltwas recrystallized from 2- propanol -methanol'-ether. Yield: 8.0g-(84.'57c).; m.p.,

,N. 8.08 I Found: c, 69.16; u, 6.67; N, 7.94

methoxy -phenyl)hy dantoin hydrochloride (TR 2986).

5,5-di(4-methoxyphenyl)hydantoin (7.8 g, 0.025 mole) was added to sodiumethoxide (0.05 mole) in 300 ml. of anhydrous ethanol and after warmingfor 30 minutes the solution was treated with l-(3-chloropropyl)-4-phenylpiperidine HCl (6.8 g, 0.025 mole). The mixturewas refluxed with stirring for 18 hours, filtered and diluted with H O.The solid was recrystallized from aqueous ethanol. Yield: 10.5 g (82%);m.p., 1634.

Calculated for C H N O C, 72.50; H, 6.87; N,

8.16 Found: C, 72.76; H, 6.70; N, 7.98 The free base g, 0.021 mole) inhot anhydrous ethanol was converted to the HCl salt with HC1 ,,/2-propanol and ether. The salt was recrystallized from methanol -ether.Yield: 9.7 g (90.5%); m.p., 227-8 (dec.).

Calculated for C H N O .HCI: C, 67.69; H, 6.60;

N, 7.64 Found: C, 67.57; H, 6.73; N, 7.55

EXAMPLE 1 1 3-13-(4-phenyl-l-piperidyl)propyl]-5-(4- bromophenyl)-5phenylhydantoin hydrochloride (TR 2987]. 5-(4-bromo-phenyl)-5-pheny1hydantoin (8.3 g, 0.025 mole) was added to sodiumethoxide (0.05 mole) in 300 ml of anhydrous ethanol and the solution waswarmed for 30 minutes and l-(3-chloropropyl)-4- phenylpiperidine HCl(6.8 g, 0.025 mole) was added. The mixture was refluxed with stirringfor 18 hours, filtered and diluted with H O. The solid wasrecrystallized from aqueous ethanol. Yield 1 1.6 g (87%); m.p., 1789.

Calculated for C H BrN O C, 65.41; H, 5.66; N,

Found: C, 65.42; N, 5.64; N, 8.16

The free base (11 g, 0.020 mole) was converted to the HCl salt with HCl/2-propanol and recrystallized from 2-propanol-methanol-ether. Yield:5.6 g (47.6%); m.p., 203-6 (dec.).

Calculated for C H BrN;,O .HCl: C, 61.22; H, 5.49;

N, 7.38 Found: C, 60.84; H, 5.36; N, 7.14

EXAMPLE 12 3-[(3-(4-pheny1-1piperidyl)propyl]-5-phenyl-5-(4- tolyl)hydantoin maleate (TR 2993). 5-phenyl-5-(4- to1yl)hydantoin (6.6 g,0.025 mole) was added to sodium ethoxide (0.05 mole) in 300 ml ofanhydrous ethanol and the solution was warmed for 30 minutes and treatedwith l-(3-chloropropy1)-4-pheny1piperidine HC1(6.8 g, 0.025 mole). Themixture was refluxed with stirring for 18 hours, filtered and dilutedwith H O. The solid was recrystallized from aqueous ethanol. Yield: 9.5g (81%); m.p., l579.

Calculated for C H N O C, 77.06; H, 7.11; N,

Found: C, 77.72; H, 7.15; N, 9.18

The free base (9.5 g, 0.020 mole) was converted to the maleate salt withexcess maleic acid in anhydrous ethanol, filtered and diluted withether. Yield: 4.3 g (36.3%); m.p., 216-7 (dec.).

6.39; N, 7.20 Found: C, 70.00; H, 6.50; N, 6.96

EXAMPLE 13 3-[3-(4-phenyl-l-piperidyl)propyl]-5,5-di(4-tolyl) hydantoin(TR 3001). 5,5-di(4-tolyl)hydantoin (7 g, 0.025 mole) was addedto'sodium ethoxide (0.05 mole) in 300 ml of anhydrous ethanol and thesolution was warmed for 30 minutes andtreated withl-(3-chloropropyl)-4-phenyl -piperidine HCl (6.8 g, 0.025 mole). Themixture was refluxed for .18 hours with stirring, filtered and dilutedwith H O. The solid was recrystallized four times with aqueous ethanoland again with aqueous acetone. Yield: 1.8 g (15%); m.p., 1545.

Calculated for C ,H N O. C, 77.31; H, 7.32; N,

8.73 Found: C, 77.07; N, 7.32; N, 8.62

EXAMPLE 14 3-[3-(4-phenyl-1-piperidyl)propyl]-5-(4- nitrophenyl)5-phenylhydantoin (TR 3012). 5-(4- nitrophenyl)-5-pheny1 -hydantoin (18g, 0.06 mole) was added to sodium ethoxide (0.12 mole) in 500 ml ofanhydrous ethanol and the solution was warmed and1-(3-chlqropropyl')-4-phenylpiperidine HCl (16.6 g, 0.06 mole) wasadded. The mixture was refluxed with stirring for 18 hours, filtered anddiluted with H O. The solid was recrystallized fromaqueousdimethylformamide-methanol. Yield: 23 g (76.7% A 5 g sample ofthe free base was twice recrystallized fromaqueous-dimethylformamide-2-propanolmethanol and again from aqueousdioxane. Yield: 1.8 g; m.p., l9 56.

Calculated for C ,,H 0N,O C, 69.86; H, 6.06; N,

1 1.24 4 Found: C, 69.44; H, 6.08; N, 11.00

EXAMPLE 15 3 [3-(4-pheny1- l -piperidyl)propyl]-5-(4- aminophenyl)-5-phenylhydantoin (TR 3021). 3-[3-(4-pheny1-l-piperidyl)propy1]-5(4-nitropheny1)- S-phenylhydantoin (17.5 g, 0.035 mole) in 200ml of glacial acetic acid and 0.6 g of Pd/C (10%) was reduced on theParr shakenThe theoretical amount of hydrogen was taken up. The mixturewas filtered and concentrated. The concentrate in aqueous methanol wasmade basic with NH,OH. The solid was recrystallized from aqueousdimethylformamide-methanol and twice from aqueous dioxane. Yield: 10.5 g(64%); m.p., 2157.

Calculated for C H N;O C, 74.33; H, 6.88; N,

l 1.96 Found: C, 74.25; H, 7.05; N, 11.73

EXAMPLE l6 5,5-diphenyl-3-[ 2-hydroxy-3-(4-phenyll-piperidyl)propyl]-hydantoin oxalate (TR 3104). A mixture of 5,5-diphenylhydantoin(10 g., 0.039 mole) and epichlorohydrin (10 g) in a solution of sodiumethoxide (0.039 mole) in 300 m1. of anhydrous EtOH was refluxed for 3hours and concentrated. The concentrate was stirred in ether, filteredand concentrated. The concentrate and 4-pheny1piperidine (6.2 g, 0.039mole) in 200 m1. of anhydrous EtOH were refluxed with stirring for 16hours and concentrated to a viscous oil. The oil and oxalic acid (5 g)were dissolved in hot acetone and let stand at room temperature. Thesolid was collected .and twice recrystallized from methanolether. Yield:8.5 g (39%); m.p., 119-121(dec.).

1 1 Calculated for C H N O C H O C, 66.54; H,

5.94; N, 7.51 Found: C, 67.08; H. 6.15; N, 7.47

EXAMPLE l7 5,5-di(4-toly1)-3-[2-hydroxy-3-(tbutylamino)propyl]-hydantoin hemioxalate (TR 3130).5,5-di(4-tolyl)hydantoin (7 g, 0.025 mole), epichlorohydrin (g) andsodium ethoxide (0.025 mole) in 200 ml. of anhydrous EtOH were refluxedwith stirring for 6 hours, filtered and concentrated to dryness invacuo. The concentrate and t-butylamine ml.) in 150 ml. of anhydrousEtOH were refluxed for 2 hours -and concentrated. The concentrate wastriturated in ether to solidify the oil and the solid was recrystallizedEXAMPLE l8 3-[3-(4-hydroxy-4-phenyl-l-piperidyl)propyl]-5,5-di 4-to1yl)hydantoin (TR 3163), 5,5'di-(4- tolyl)hydantoin (6 g, 0.02 mole) wasadded to a solution of sodium ethoxide (004 mole) in 350 ml-of anhydrousethanol and the solution was refluxed for-30 min. 1-( 3-chloropropyl)-4-hydroxy-4phenyl-piperidine HCl (5.5 g, 0.02 mole) was added and themixture was refluxed for 5 hours, then diluted with water. The solid wascollected and recrystallized from aqueous ethanol. Yield: 6 g (56.5%m.p., 1812.

Calculated for C,,,H ,-,N;,O C, 74.83; H, 7.09; N,

8.44 Found: C, 75.22; H, 7.29; N, 8.42 The free base (5.7 g, 0.01 1mole) was converted to the HCl salt with HCl (g) in2-propanol-ethylacetate and recrystallized from2-propanol-me'thanolethylacetate. Yield: 4.1 g (67.2%); m.p., 230 1(dec.).

Calculated for C;,,H -,N;,O .H Cl: C, 69.72;

N, 7.87 Found: C. 69.67; H, 6.77: N, 7.58

EXAMPLE 19 Antiarrhythmic Activity The antiarrhythmic activity of thecompounds of this invention, specifically those enumerated in the Simmary and presented as the above examples, compared to that ofdiphenylhydantoin (1), 3-(3- diethylaminopropyl)-5,S-diphenylhydantoin(11). 3-3; (1-piperidyl)-propyl)-5,5-diphenylhydantoin (11 1), and 3-(3-morpholinopropyl )-5,S-diphenylhydantoiri (1V). V

The tests compounds were administered to groups consisting of 5 mice invarying intraperitoneal doses. Ten minutes after administration of agiven dose of a compound, a-mouse was transferred to a covered 300 mlglass beaker which contained a wad of cotton saturated with about 20 mlof chloroform. The animal was observed closely and removed from thebeaker immediately after respiratory arrest. The heart was quicklyexposed by making an incision through the abdomen,

diaphragm, thorax and pericardium for visual inspection of ventricularrate and rhythm. Ventricular contractions were counted for 30 seconds.According to the procedure reported by Lawson, (J. Pharmacol. Exp.Therap., 160: 22 [1968]) animals with a ventricular rate not exceeding100 contractions during the 30 second observation period were consideredprotected. Results obtained with each dose were used to calculate themean effective doses (EDsn) after the method of Litchfield and Wilcoxon(J. Pharmacol. Exp. Therap. 96: 991 13 [1949]). Deaths occurring afteradministration of each close but before exposure to chloroform werenotedin order to determine the minimum lethal dose for each compound. Theresults are shown in Table A.

In Table A, the compounds of this invention are listed by the arabicnumeral assigned in the Summary and the above corresponding ExampleNumber; the

Roman numerals refer to the compounds so designated above in thisExample and in the Description of the Prior Art.

Table A Compound ED CL) MLD MLD/ED mg/kg g/ g 1(MA 1586) 16.4(8-35) 1609,77 2(MA 1598) 13.5(7-26) 320 23.71 4(TR 2913) 96.0(50-182) 178 1.855(TR 2916) 5.8(3-11) 31 5.35

6(TR 2921) 9.4(6-15) 10.62 8(TR 2984) 75.0(39-142) 178 2.28 10(TR 2986)34,0(18-63) 178 5.24 11(TR 2987) 33.5(22-52) 100 2.98 12(TR 2993)19.5(1l-55) 100 5.13 13(TR 3001) 4.5(2-12) 100 22.20 14(TR 3012)10.5(5-21) 100 9.52 15(TR 3021) 3.-l( 2-7) 100 29.40 18(TR3163)24.0(11-56) 100 4.17

ED,-.0 (95% C1.) is the mean effective dose in mg/kg. intraperitoneally;

95% CL is the confidence limits in mg/kg.

MLD is the Minimum Lethal Dose in mg/kg. intraperitoneally.

MLD/EDsu is the Therapeutic Index calculated with Minimum Lethan DoseData.

EXAMPLE 20 The effect of the compounds of this invention on therefractory period in the atrium was studied and compared to thathydantoin according to the procedure described by Dawes (Brit. J.Pharmacol., l: 90, [1946]).

Guinea pig atria, suspended in an isolated organ chamber, werestimulated electrically at increasing frequencies while the resultingmechanical contractions were recorded. The minimum interval between twoconsecutive stimuli necessary for eliciting a mechanical response wasdetermined before and after incubation with varying concentrations ofthe test compounds. The minimum interval thus determined is an indirectmeasure of the refractory period in the tissue, and a prolongation ofthis interval indicates an increased refractory period. From theincrease in minimum interval observed with each concentration, theamount necessary for increasing the interval by 50 percent over controlvalues (EC was determined for each compound. As shown in Table B, thecompounds of this invention (designated by the corresponding examplenumber and arabic numeral assigned in the Summary) are more effective inprolonging the atrial refractory period (thus causing less cardiacdepression) than the parent com pound, diphenylhydantoin (designated asDPH).

Table B Compound Ecmi. mcg/ ml 1(MA 1586) 2(MA1598) 4(TR 29]. 5(TR Z916)6(TR Z921) 8(TR 2984) 10(TR 2986) ll(TR 2987) 13(TR 2993) 13(TR 3001)14(TR 30l2) 15(TR 3021) 18(TR3I63) DPH (l) What is claimed is: l. Acompound of the formula 14 pipcrazinyl)propyl]-5,5-diphenylhydantoinmaleate.

3. A compound as in claim 1,3-[3-(4-phenyl-lpiperidyl)propyll-5,5-diphenylhydantoin.

4. A compound as in claim 1,2-[2-(4-phenyl-lpiperidyl)ethyl]-5,5diphenylhydantoin HCl.

5. A compound as in claim 1, 5, 5-diphenyl-3-[2-(4- phenyl-l2,3,o-tetrahydropyridyl )ethyllhydantoin HCl.

6. A compound in claim 1, 5,5-diphenyl-3-[3- (4-hydroxy-4-phcnyll-piperidyl )propyl]hydantoin HCl.

7. A compound as in claim 1, 5.5-diphenyl-3-[2-(4-hydroxy-4-phenyl-l-piperidyl)ethyl]hydantoin HCl.

8. A compound as in claim 1,3-[3-(4-phenyl-lpiperidyl)propyl]-5,5-di(4-chlorophenyl)hydantoin HCl.

9. A compound as in claim 1,3-l3-(4-phenyl-lpiperidyl)propyl]-5-(4-methoxyphenyl)-5- phenylhydantoinHCl.

10. A compound in claim 1,3-[3-(4-phenyl-lpiperidyl)propyl]-5,5-di(4-methoxyphenyl)hydantoin HCl.

11. A compound as in claim 1,3-[3-(4-phenyl-lpiperidyl)propyll-5-(4-bromophenyl)-5- phenylhydantoinHCll 12. A compound as in claim 1,3-[3-(4-phenyl-lpiperidyl)propyl]-5-phenyl-5-(4-tolyl)hydantoin malcate.

13. A compound as in claim 1, 3-[3-(4phenyl-I-piperidyhpropyl]-5,5-di(4-t0lyl)hydantoin.

14. A compound as in claim 1.3-[3-(4-phenyl-lpiperidyl)propyl]-5(4-nitrophenyl )-5- phenylhydantoin.

15. A compound as in claim 1. 3-[3-(4-phenyl-lpiperidyl )propyl]-5-(4-aminophenyl )-5- phenylhydantoin.

16. A compound as in claim 1, 3-[3-(4-hydroxy-4-phenyl-l-piperidyl)propyl]-5,5-di-(4-tolyl)hydantoin.

1. A COMPOUND OF THE FORMULA
 2. A compound as in claim 1,3-(3-(4-phenyl-1-piperazinyl)propyl)-5,5-diphenylhydantoin maleate.
 3. Acompound as in claim 1,3-(3-(4-phenyl-1-piperidyl)propyl)-5,5-diphenylhydantoin.
 4. A compoundas in claim 1, 2-(2-(4-phenyl-1-piperidyl)ethyl)-5,5-diphenylhydantoin .HCl.
 5. A compound as in claim 1, 5,5-diphenyl-3-(2-(4-phenyl-1,2,3,6-tetrahydropyridyl)ethyl)hydantoin . HCl.
 6. A compound as in claim 1,5,5-diphenyl-3-(3-(4-hydroxy-4-phenyl-1-piperidyl)propyl)hydantoin .HCl.
 7. A compound as in claim 1,5,5-diphenyl-3-(2-(4-hydroxy-4-phenyl-1-piperidyl)ethyl)hydantoin . HCl.8. A compound as in claim 1,3-(3-(4-phenyl-1-piperidyl)propyl)-5,5-di(4-chlorophenyl)hydantoin .HCl.
 9. A compound as in claim 1,3-3-(4-phenyl-1-piperidyl)propyl)-5-(4-methoxyphenyl)-5-phenylhydantoin. HCl.
 10. A compound as in claim 1,3-(3-(4-phenyl-1-piperidyl)propyl)-5,5-di(4-methoxyphenyl)hydantoin .HCl.
 11. A compound as in claim 1,3-(3-(4-phenyl-1-piperidyl)propyl)-5-(4-bromophenyl)-5-phenylhydantoin .HCl.
 12. A compound as in claim 1,3-(3-(4-phenyl-1-piperidyl)propyl)-5-phenyl-5-(4-tolyl)hydantoin .maleate.
 13. A compound as in claim 1,3-(3-(4-phenyl-1-piperidyl)propyl)-5,5-di(4-tolyl)hydantoin.
 14. Acompound as in claim 1,3-(3-(4-phenyl-1-piperidyl)propyl)-5-(4-nitrophenyl)-5-phenylhydantoin.15. A compound as in claim 1,3-(3-(4-phenyl-1-piperidyl)propyl)-5-(4-aminophenyl)-5-phenylhydantoin.16. A compound as in claim 1,3-3-(4-hydroxy-4-phenyl-1-piperidyl)propyl)-5,5-di-(4-tolyl)hydantoin.